We are investigating the role of Type-2 immunity in several models of fibrosis that affect the lung, liver, and intestine to determine whether there are common as well as distinct mechanisms of fibrosis in various organ systems and/or fibrotic diseases. Several distinct in vivo models of organ fibrosis are employed, including mouse models of chronic asthma, inflammatory bowel disease, and obesity induced steatosis. Progress was made in following areas over the past year. 1. In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced. 2. Asthma is a chronic disorder, characterised by episodic airway hyperresponsiveness (AHR), and remodelling with variable degrees of eosinophilic and neutrophilic inflammation. Asthma causes significant morbidity and mortality, and approximately 10% of patients have disease that is resistant to current therapies. This group consumes 50 to 60% of health care costs attributed to asthma, underscoring the necessity to discover new therapies. The clinical expression of asthma is heterogeneous with several distinct phenotypes identified. Identifying the molecular mechanisms driving subtypes of asthma has the potential to reveal drug targets, biomarkers to predict treatment response, and appropriately target therapy, as evidenced by recent clinical studies of Th2 cytokine antagonists. In addition to the Th2 pathway, attention has focused on Th17 cytokines as candidate alternative drivers of severe asthma pathophysiology. IL-17A and F can amplify selected NF-&#954;B dependent signalling pathways such as those induced by TNF&#945;, a cytokine upregulated in asthmatic airways, and are further upregulated following allergen challenge and experimental rhinovirus infection. In particular, IL-17A may contribute to neutrophilic airway inflammation via upregulation of CSF3 and CXCL chemokines, mucus gland hyperplasia, AHR and corticosteroid resistance. Therapeutic strategies targeting Th2 and Th17 inflammatory pathways are currently under active investigation in asthma. However, the nature and extent of the activity of these two pathways in individual patients is unclear. Th2 cytokines can negatively regulate Th17 cytokine expression, and inhibiting Th2 cytokines in vitro or in vivo has the potential to increase IL-17A production and IL-17A-dependent airway inflammation. The cross-talk between Th2 and Th17 pathways is therefore complex, and it has been proposed that targeting Th2 cytokines might promote corticosteroid resistant IL-17-dependent neutrophilic airway inflammation. In this project, we showed that Th2 and Th17-related gene expression signatures are mutually exclusive in the airways of asthma patients, but both are associated with eosinophilic inflammation. Also, using an in vivo preclinical model of HDM-induced asthma, we show that therapeutic targeting of Th2 and Th17 cytokines, respectively, can lead to amplification of activity of the opposing pathway. Thus, therapeutics that disrupt both pathways simultaneously may show increased efficacy across a diverse patient population.